Use of serotonin antagonists for treating fibromyalgia

ABSTRACT

The invention is directed to the use of 5HT 3  antagonists of formula I ##STR1## wherein the substituents are as defined herein.

This application is a 371 of PCT/EP95/01264, filed Apr. 6, 1995.

This invention relates to a new use of 5HT₃ antagonists.

These compounds are also referred to hereinafter as compounds of theinvention.

5HT₃ antagonists are a class of compounds which block 5HT₃ receptors.Examples include compounds disclosed in Belgian patents 897117, 900425and 901274. These compounds are described therein as being 5HT₃ receptorantagonists or serotonin M receptor antagonists (serotonin M receptorshave been reclassified as 5HT₃ receptors).

Other classes of the compounds of the invention are known from e.g.European patent publications 13138A, 200444A, and 214772A and BritishPatent publication 2153821.

5HT₃ antagonists from various sources have been published for a widevariety of uses, for example for the treatment of visceral pain,migraine, vascular and cluster headache, trigeminal neuralgia,arrhythmia, serotonin-induced gastro-intestinal disorders, includingemesis induced by anti-cancer agents, anxiety, stress-relatedpsychiatric disorders, depression, cognitive disorders, socialwithdrawal, panic attacks, agoraphobia, lung embolism, rhinitis orserotonin-induced nasal disorders, for increasing vigilance or fortreating dependency induced by dependence-inducing agents. Some havebeen commercially introduced for the treatment of emesis.

It has now surprisingly been found that the compounds of the inventionexert a marked improvement in patients suffering from fibromyalgia,which affects the major symptoms including pain as well as thefunctional and vegetative disorders and lasts beyond the time oftreatment.

Fibromyalgia (also known as fibrositis or generalized tendomyopathy) isa very common disease which is characterized by pains and stiffness inthe various regions of the locomotory apparatus, particularly in theregion of the tendon insertions and tendon sheaths, which are verysensitive to pressure, furthermore by functional and vegetativedisorders as well as psychopathological findings such as depressiveconditions and neuroses.

Examples of functional symptoms are sleep disorders, headache, migraine,globus sensation, functional breathing and cardiac complaints,gastrointestinal disorders and dysuria. Examples of vegetative symptomsare cold extremities, hyperhidrosis, dryness of mouth, dermatographia,tremor, respiratory arrhythmia and orthostatic problems.

The treatment of fibromyalgia is very problematic and unsatisfactory. Aneffective therapy of the disease is not available yet. Attempts toattenuate the pain symptoms using analgesics and non-steroidalanti-inflammatories were unsuccessful. Muscle relaxants showed limitedactivity at very high dosages which induced considerable side effectsand had to be stopped. Antidepressive drugs such as amitriptyline werealso proposed and showed some activity in a sub-group of patients, whichhowever decreased rapidly.

The compounds of the invention include compounds of formula I ##STR2##wherein R₁ is hydrogen, halogen, hydroxy, alkoxy(1-4C), amino,alkyl(1-4C)amino or dialkyl (1-4C)amino,

R₂ is hydrogen, alkyl(1-7C), alkenyl(3-6C), alkynyl(3-10C),cycloalkyl(3-7C), cycloalkyl(3-7C)alkyl(1-4C), phenyl,phenylalkyl(1-3C), alkyl(1-6C)carbonyl, alkyl(1-6C)oxycarbonyl,carbamoyl, sulfamoyl or mono- or dialkyl(1-6C)-carbamoyl or -sulfamoyl,

X is CH or N and

Y is NR₃ or O, R₃ being hydrogen or alkyl(1-6C), or

X+Y together are C-A-N or C-A-CH, wherein A is CH═CH or -(CH₂)_(m) -, mbeing 2 or 3,

n is 0, 1 or 2 and

Z is a radical of formula (a) ##STR3## wherein o is 0, p is 0, 1 or 2and q is 0, 1 or 2, or o is 1, p is 0 and q is 0 or 1, and

R₄ is hydrogen, alkyl(1-7C), cycloalkyl(3-6C), phenylalkyl(1-4C)optionally mono- or disubstituted by halogen, alkyl(1-4C) oralkoxy(1-4C),

or a radical of formula (b) ##STR4## wherein o' is 1, 2 or 3, p' is 0 or1 and q' is 0 or 1, or a radical of formula (c) or (d) ##STR5## whereinone of R₅, R₆ and R₇ is hydrogen, alkyl(1-6C), cycloalkyl(3-7C),alkenyl(2-6C), phenyl or phenylalkyl(1-3C) and the 2 othersindependently are hydrogen or alkyl(1-6C), provided that Z is not (d)when n is 0 and Y is NR₃ or (with X) N-A-C,

in free form or in pharmaceutically acceptable salt or complex form.

R₁ is preferably hydrogen or methoxy.

R₂ is preferably hydrogen or alkyl(1-7C).

In R₂, alkyl(1-7C) is preferably alkyl(1-4C), more preferably methyl,alkenyl(3-6C) is preferably alkenyl(3-4C), alkynyl(3-10C) is preferablyalkynyl(3-4C), cycloalkyl(3-7C) is preferably cycloalkyl(3-6C),cycloalkyl(3-7C)alkyl(1-4C) is preferably cycloalkyl(3-6C)methyl,phenylalkyl(1-3C) is preferably benzyl, alkyl(1-6C)carbonyl ispreferably alkyl(1-4C)carbonyl, alkyl(1-6C)oxycarbonyl is preferablyalkyl(1-4C)oxycarbonyl and dialkyl(1-6C)carbamoyl and -sulfamoyl arepreferably dimethylcarbamoyl and -sulfamoyl.

R₃ is preferably hydrogen or methyl.

R₄ in (a) is preferably hydrogen or alkyl(1-4C), more preferably methyl.

Preferably one of R₅, R₆ and R₇ in (c) and (d) is methyl and the twoothers are hydrogen. More preferably R₅ is methyl and R6 and R₇ arehydrogen. When X+Y together are C-(CH₂)_(m) -CH, m is preferably 2.

In (a) preferably o is 0 and p and q are 1 or p is 1 and q is 0.

When Z is of formula (a) or (b), n is preferably 0. When Z is of formula(c) or (d), n is preferably 1.

In a group of compounds of formula I, R₁ is alkyl(1-4C), R₂ is hydrogen,X is CH, Y is O or NH, n is 0 and Z is of formula (a') ##STR6## whereinR'₄ is methyl, ethyl or propyl and q" is 0, 1 or 2.

Depending on the nature of the substituents defined above, asymmetriccarbons may be present in the molecule. This is the case for examplewhen X+Y together are C-A-CH. All optical isomers and their mixturesincluding the racemic mixtures are part of the present invention.

Furthermore depending on the nature of the Y-(CH₂)_(n) -Z radical, thecompounds may present the exo or endo configuration. The exo/endonomenclature is well known in the literature. Again, both exo and endoforms and their mixtures are part of the present invention.

The endo isomers are preferred.

The compounds of formula I may exist in free form or in salt form.Suitable salt forms include acid addition salts and quaternary ammoniumsalts.

The compounds of the invention may be chosen from the followingcompounds:

Indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclo3,2,1!-oct-3yl-ester (the hydrochloride is also known as tropisetron,hereinafter compound A);

benzo b!thiophen-3-yl-carboxylic acid-endo-9-methyl-azabicyclo 3,3,1!)non-3-yl-ester;

5-fluoro-1-methyl-indol-3-yl-carboxylic acid-endo-9-methyl-9-aza-bicyclo3,3,1!non-3-yl-ester;

1,2,3,9-tetrahydro-9-methyl-3-(2-methyl-1H-imidazol-1-yl)-methyl!-4H-carbazol-4-one (also known asondansetron; hereinafter compound B);

1-methyl-indazol-3-yl-carboxylic acid-9-methyl-9-aza-bicyclo-3,3,1!non-3α-yl-amide (also known as granisetron);

endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo3,3,1!)non-4-yl)-benzamide;

3- 5-methyl-1H-imidazol-4-yl!-1-(1-methyl-1H-indol-3-yl)-1-propanone;

N-(1-azabicyclo 2,2,2!oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide (also known as azasetron);

N-(endo-8-methyl-8-azabicyclo3,2,1!oct-3-yl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-carboxamide:

7-methoxy-1H-indol-3-carboxylic acid-(1αH,5αH)-8-methyl-8-aza-bicyclo3,2,1!oct-3α-yl-ester;

the compound known as GR 87442.

Further preferred 5HT₃ antagonists include:

4,5,6,7-tetrahydro-5- (1-methyl-indol-3-yl)carbonyl!benzimidazole;

(+)-10-methyl-7-(5-methyl-1H-imidazol-4-ylmethyl)-6,7,8,9-tetrahydropyrido 1,2-a!indol-6-one; and

N-(1-ethyl-2-imidazolin-2-yl-methyl)-2-methoxy-4-amino-5-chlorobenzamide.

The unexpected efficacy of the compounds of the invention in thetreatment of fibromyalgia is established in clinical trials.

In these clinical trials, ambulatory patients suffering from clinicallydiagnosed fibromyalgia are tested using the 10 cm visual analogue scalefor patient self rating (0 =no pain; 10 =severe pain), the "pain score"(pain severity scale) at various body sites and the digital dolorimetertenderness score at 24 tender points, according to methods described byW. Muller and J. Lautenschlager in Z. Rheumatol 49: 11-21 (1991). Atender point is a localized area of intense pain on deep palpation.Additionally the patients are asked to fill out a form with respect tofunctional/vegetative symptoms which are evaluated as marked (3),moderate (2), mild (1) or absent (0). These symptoms include:

cold hands or feet

dry mouth

increased sweating

dizziness

trembling

sleep disturbances

gastric disturbances

intestinal disturbances, constipation/diarrhea

lumpiness in the throat

periodic respiratory distress (without previous exertion)

tachycardia/arrhythmia

sleepiness, tingling or other abnormal sensations in body parts

pain on micturation

headache or migraine

paresthesia

The statistical analysis of the results is effected according to theWilcoxon test or the Mann-Withney U-test.

In one such trial the compound of the invention was compound A and 17patients were treated orally during 5 days, with 2×5 mg daily. Eight ofthose were found to be very good responders (≧40% improvement in thevisual analogue score), with the following results:

A significant improvement was observed in the visual analogue scale(p=0.0142), in the pain score (p=0.014), in the dolorimetry (p=0.0208for the average pressure triggering pain and p=0.0346 for the number oftender points) and in the evaluation of the vegetative symptoms(p=0.0109).

In another trial with compound A, 40 patients were treated. A firstgroup of 20 patients received 2×5 mg daily during 10 days, a secondgroup of 20 patients received 3×5 mg daily during 10 days. Eighteenpatients (9 from each group) were found to be very good responders (≧40%improvement in the visual analogue score or in the pain score) with thefollowing results:

A significant improvement was observed in the visual analogue scale(p<0.0003, the score decreasing from 7.6 to 2.6), in the pain score(which decreased from 55.8 to 22.6) and in the dolorimetry (p<0.06 forthe average pressure triggering pain, which passed from 1.91 to 2.24 kp,and p<0.02 for the number of tender points which passed from 19.4 to14.2).

Also the vegetative and functional symptoms improved significantly. Forexample significative improvements were observed in the symptoms sleepdisturbances (p<0.006), cold hands or feet (p<0.002), headaches(p<0.03), paresthesia (p<0.008), tachycardia/arrhythmia (p<0.006) andperiodic respiratory distress (p<0.006).

Surprisingly in these trials the achieved improvement of both pain andvegetative symptoms lasted several weeks after therapy.

In still another trial the compound of the invention was compound B anda double-blind study was carried out with 20 patients. The patientsreceived orally 2×8 mg/day of the compound during 5 days and after apause of 2 days, 2×500 mg/day paracetamol during 5 days (or vice-versadepending on randomization). Eleven patients were found to be very goodresponders to compound B according to the definition given above, withthe following results:

A significant improvement was observed in the visual analogue scale(p=0.003), in the pain score (p=0.022), in the dolorimetry (p=0.008 forthe average pressure and p=0.018 for the number of tender points) and inthe evaluation of the vegetative symptoms (p=0.003).

Under paracetamol, no significant improvement was observed in the visualanalogue scale and in the pain score. In the dolorimeter, the resultswere significantly negative (decrease of pressure triggering pain,p=0.028; increase of number of tender points, p=0.029).

Again, the good results achieved with compound B lasted several weeksafter treatment, during which the general condition of the patients wassignificantly improved.

These trials are indicative for a long-lasting and disease-modifying (asopposed to merely symptomatic) activity of the compounds.

The compounds of the invention are therefore useful in the treatment offibromyalgia.

For this indication the appropriate dosage will, of course, varydepending upon, for example, the compound employed, the host, the modeof administration and the nature and severity of the condition beingtreated. An indicated daily dosage is in the range usually used forknown indications such as emesis and is typically from about 0.05 toabout 50 mg, conveniently administered, for example, in divided doses upto four times a day, in unit dosage form or in sustained release form.

The compounds of the invention may be administered by any conventionalroute, in particular enterally, preferably orally e.g. in the form oftablets or capsules, or parenterally, e.g. in the form of injectablesolutions or suspensions.

The present invention also provides pharmaceutical compositionscomprising the compounds in association with at least one pharmaceuticalcarrier or diluent for use in the treatment of fibromyalgia. Suchcompositions may be manufactured in conventional manner. Unit dosageforms may contain for example from about 0.01 mg to about 25 mg of thecompound.

The invention further provides the use of a compound of the inventionfor the manufacture of a pharmaceutical composition for the treatment offibromyalgia.

The invention futhermore provides a method for the treatment offibromyalgia in a subject in need of such treatment, which comprisesadministering to said subject a therapeutically effective amount of acompound of the invention.

We claim:
 1. A method for treating fibromyalgia comprising administeringto a subject in need of such treatment a therapeutically effectiveamount of a compound of formula I: ##STR7## wherein R₁ is hydrogen,halogen, hydroxy, alkoxy(1-4C), amino, alkyl(1-4C)amino ordialkyl(1-4C)amino,R₂ is hydrogen, alkyl(1-7C), alkenyl(3-6C),alkynyl(3-10C), cycloalkyl(3-7C), cycloalkyl-(3-7C)alkyl(1-4C), phenyl,phenylalkyl(1-3C), alkyl(1-6C)carbonyl, alkyl-(1-6C)oxycarbonyl,carbamoyl, sulfamoyl or mono- or dialkyl(1-6C)carbamoyl or -sulfamoyl, Xis CH or N and Y is NR₃ or O, R₃ being hydrogen or alkyl(1-6C), or X+Ytogether are C-A-N or C-A-CH, wherein A is CH═CH or (CH₂)_(m) -, m being2 or 3, n is 0, 1 or 2 and Z is a radical of formula (a) ##STR8##wherein o is 0, p is 0, 1 or 2 and q is 0, 1 or 2, or o is 1, p is 0 andq is 0 or 1, andR₄ is hydrogen, alkyl(1-7C), cycloalkyl(3-6C),phenylalkyl(1-4C) optionally mono- or di- substituted by halogen,alkyl(1-4C) or alkoxy(1-4C), or a radical of formula (b) ##STR9##wherein o' is 1, 2 or 3, p' is 0 or 1 and q' is 0 or 1, or a radical offormula (c) or (d) ##STR10## wherein one of R₅, R6 and R₇ is hydrogen,alkyl(1-6C), cycloalkyl(3-7C), alkenyl(2-6C), phenyl orphenylalkyl(1-3C) and the 2 others independently are hydrogen oralkyl(1-6C), provided that Z is not (d) when n is 0 and Y is NR₃ or(with X) N-A-C,in free form or in pharmaceutically acceptable salt orcomplex form.
 2. A method according to claim 1 wherein the 5-HT₃antagonist is indol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclo3,2,1!-oct-3-yl-ester, in free form or pharmaceutically acceptable saltor complex form.
 3. A method according to claim 1 wherein the 5-HT₃antagonist is 1,2,3,9-tetrahydro-9-methyl-(2-methyl-1H-imidazol-1-yl)-methyl!-4H-carbazol-4-one, in free form orpharmaceutically acceptable salt or complex form.